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Antigen-specific Cytotoxic T Cells in the Treatment of Opportunistic Infections

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ClinicalTrials.gov Identifier: NCT03159364
Recruitment Status : Recruiting
First Posted : May 18, 2017
Last Update Posted : July 10, 2018
Sponsor:
Information provided by (Responsible Party):
Lung-Ji Chang, Shenzhen Geno-Immune Medical Institute

Brief Summary:
Epstein Barr Virus (EBV) or Cytomegalovirus (CMV) infection results in significant morbidity and mortality in hematopoietic stem cell transplantation (HSCT) patients. HSCT patients often face opportunistic infections due to the immunosuppressive state during transplantation. Antimicrobial drugs are usually used for prophylactic purposes and for treatment after early detectable infections. Unfortunately, some patients develop resistance to such drug treatment. In addition to HSCT patient, immune compromised patient may also be victim to opportunistic infections. Many infections can be effectively managed by functional immune recovery. In this study, the safety and efficacy of microbial-specific cytotoxic T lymphocytes (CTLs) will be investigated.

Condition or disease Intervention/treatment Phase
Pathogen Infection EBV Infection CMV Infection Adenovirus Infection BKV Infection Fungus Infection Tuberculosis Biological: pathogen-specific CTLs Phase 1 Phase 2

Detailed Description:

Background:

Opportunistic infections are major causes of transplant-related morbidity and mortality in immunosuppressed patients, especially in the early post-transplant period. CMV, EBV, adenovirus (AdV), BK virus (BKV) and other viruses or non-viral pathogens may lead to life-threatening infections after transplantation.

Adoptive immunotherapy with cytotoxic T lymphocytes (CTLs) reactive with specific microbial antigens has proven to be effective without stimulating acute graft-versus-host disease (GVHD) owing to the significantly reduced nonspecific alloreactivity. This study aims to evaluate the safety and efficacy of treating opportunistic infections with microbial-specific CTLs in immune compromised patients.

Objective:

Primary study objectives: Infusion of autologous or allogenic pathogen-specific CTL to patients by I.V., to evaluate the safety.

Secondary study objectives: To evaluate the anti-microbial efficacy of IV-infused autologous or allogenic pathogen-specific CTLs.

Design:

Peripheral blood mononuclear cells (PBMC) will be obtained through apheresis. T cells from PBMC will be activated and enriched by dendritic cells with pathogen specific antigens. Cell preparation time is approximately 12-17 days. Subject will receive infusions of 1x105~1x106 cells/kg body weight of CTLs via IV infusion. Patients are followed weekly for one month after the infusion, monthly for 3 months, and then every 3 months until the trial ends.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Multicenter Trial of Antigen-specific Cytotoxic T Cells in the Treatment of Opportunistic Infections
Actual Study Start Date : July 15, 2017
Estimated Primary Completion Date : July 31, 2020
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Infusion of pathogen-specific CTLs
Repetitive CTL infusions to treat microbial infections
Biological: pathogen-specific CTLs
Patients will receive approximately 1x10^5~1x10^6 CTLs/kg as a single infusion via IV injection and may receive additional infusions.




Primary Outcome Measures :
  1. Using CTCAE 4 standard to evaluate the level of adverse events after receiving autologous or allogenic pathogen-specific CTL infusion [ Time Frame: 24 weeks ]
    to evaluate the level of adverse events with CTCAE 4

  2. Viral load change after Virus-CTL infusion [ Time Frame: 2 months ]
    The viral load response to the Virus-CTL infusion will be assessed by specific PCR of peripheral blood after infusion.


Secondary Outcome Measures :
  1. The incidence of CTL infusion syndrome mimicking grade Ⅱ~Ⅳ GVHD within 30 days after the last dose of CTL infusion [ Time Frame: 1 months ]
  2. Reconstitution of anti-microbial immunity monitored by flow cytometry [ Time Frame: 6 months ]
  3. Number of patients with chronic GVHD-like symptom [ Time Frame: 6 months ]


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Ages Eligible for Study:   6 Months to 80 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Subjects with or without hematopoietic stem cell transplantation / organ transplant recipients need to meet the following conditions:

  • Evidence of CMV, EBV, ADV, BKV or known pathogen infection (viral DNA, immunohistochemical cytology positive); contraindications or invalid to anti-microbial drugs.
  • Subjects with virus DNA increased in the 2 consecutive peripheral blood samples (≥ 1000 genomic copies/ml blood) at least 24 hours apart.
  • Initial hematopoietic reconstitution: neutrophils (ANC) ≥ 0.5x109 / L, platelet (PLT) ≥ 20x109 / L.
  • Patients with pahogen disease (organ/ tissue infiltration) symptoms, fever, diarrhea, or lymphadenopathy, regardless of the level of peripheral blood virus DNA, and confirmed by the presence of viral DNA or microbial antigens within body fluid or biopsy.
  • The subject / guardian has signed a written consent form before any trial begins.

Proper renal and hepatic functions (ULN denotes "upper limit of normal range"):

  • Creatinine ≤ 2*ULN.
  • Bilirubin ≤ 2*ULN.
  • SGOT ≤ 3*ULN.
  • SGPT≤ 3*ULN.

If CTL is not from the patient's own, then the provider of CTLs needs to meet the following criteria:

  • Did not receive chemotherapy or radiotherapy within 4 weeks prior to blood collection, and did not take any steroids for the previous week, did not use Penicillin or β-lactam antibiotics, or the lowest dose of other antibiotics.
  • White blood cells ≥ 3,500 / μl, lymphocytes ≥ 750 / μl.
  • Obtain a signed informed consent from the patient and / or the guardian or the donor of the BMT recipient.
  • Human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) or tuberculosis (TB) test is negative.
  • Physical examination in line with the standard of healthy blood donors.

Exclusion Criteria:

  • Subject infected with HCV (HCV antibody positive), HBV (HBsAg positive), HIV (HIV antibody positive), or HTLV (HTLV antibody positive).
  • GVHD (graft-versus-host disease) performance score at II-IV.
  • Subject is albumin-intolerant.
  • Subject with life expectancy less than 4 weeks.
  • Subject participated in other investigational somatic cell therapies within past 30 days.
  • Subject with positive pregnancy test result.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03159364


Contacts
Contact: Lung-Ji Chang, PhD +86(755)8672 5195 c@szgimi.org

Locations
China, Guangdong
Shenzhen Geno-immune Medical Institute Recruiting
Shenzhen, Guangdong, China, 518000
Contact: Lung-Ji Chang, PhD    86-755-86725195    c@szgimi.org   
Sponsors and Collaborators
Shenzhen Geno-Immune Medical Institute
Investigators
Principal Investigator: Lung-Ji Chang, PhD Shenzhen Geno-Immune Medical Institute

Responsible Party: Lung-Ji Chang, President, Shenzhen Geno-Immune Medical Institute
ClinicalTrials.gov Identifier: NCT03159364     History of Changes
Other Study ID Numbers: GIMI-IRB-17009
First Posted: May 18, 2017    Key Record Dates
Last Update Posted: July 10, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Lung-Ji Chang, Shenzhen Geno-Immune Medical Institute:
CTL
Virus CTL
Fungus CTL
TB CTL

Additional relevant MeSH terms:
Cytomegalovirus Infections
Infection
Communicable Diseases
Tuberculosis
Opportunistic Infections
Adenoviridae Infections
Epstein-Barr Virus Infections
Mycoses
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Virus Diseases
Parasitic Diseases
Herpesviridae Infections
DNA Virus Infections
Tumor Virus Infections